A physiologically based pharmacokinetic (PB-PK) model for 1,2-dichlorobenzene linked to two possible parameters of toxicity
A physiologically based pharmacokinetic (PB-PK) model for 1,2-dichlorobenzene linked to two possible parameters of toxicity
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DOI：
10.1006/taap.1997.8184
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发表时间：
1997-08-01
影响因子：
3.8
通讯作者：
VanBladeren, PJ
中科院分区：
文献类型：
--
作者：
Hissink, AM;VanOmmen, B;VanBladeren, PJ
开发了大鼠1，2-二氯苯（1，2-DCB）的生理药代动力学（PB-PK）模型。使用人体外参数（包括用人微粒体测定的V-max和K-m），针对人体情况调整该模型。为了进行比较，将大鼠的V-max和K-m值按异速生长比例缩放至人类情况。该模型用于两个方面：（1）急性肝毒性与体外形成的反应性代谢产物（环氧化物）的量有关。对于大鼠，使用体外参数预测暴露于毒性剂量水平（250 mg/kg bw）后体内环氧化物代谢物的肝脏浓度。对于人，假设肝脏中存在浓度-效应关系，预测获得与大鼠相同的反应性代谢物毒性肝脏浓度所需的剂量水平。可以得出结论，即使在诱导氧化步骤后，由于代谢饱和和伴随的1，2-DCB在脂肪中蓄积，也未达到该浓度。(2)肝毒性与肝脏中谷胱甘肽（GSH）耗竭有关。在该模型中，描述了通过代谢（基于体内和体外数据）和正常周转消耗肝脏GSH。通过比较模型预测值与在两个剂量水平（50和250 mg/kg bw）下进行的GSH耗竭研究结果，进行了体内验证。随后，使用人体体外代谢数据估计了人体1，2-DCB代谢产物的GSH消耗量。假定人肝脏中的GSH周转与大鼠中的相同。看来，在250毫克/公斤的剂量水平，肝GSH完全耗尽后10小时的人，而大鼠的最大消耗75%的预测，15小时后。所提出的模型提供了一个定量的工具，用于评估人类风险的两种不同的毒性情况下，即共价结合的活性代谢物和GSH的消耗。(C)北京：科学出版社.
A physiologically based pharmacokinetic (PB-PK) model was developed for 1,2-dichlorobenzene (1,2-DCB) for the rat. This model was adjusted for the human situation, using human in vitro parameters, including a V-max and K-m determined with human microsomes. For comparison, the V-max and K-m values from the rat were scaled allometrically to the human case. The model was used in two ways: (1) Acute hepatotoxicity was related to the amount of reactive metabolites (epoxides) formed in vitro. For rats, the hepatic concentration of epoxide metabolites in vivo after exposure to a toxic dose level (250 mg/kg bw) was predicted using in vitro parameters. For man, the dose level needed to obtain the same toxic liver concentration of reactive metabolites as in rat was predicted, assuming a concentration-effect relationship in the liver. It could be concluded that this concentration is not reached, even after induction of the oxidation step, due to saturation of metabolism and a concomitant accumulation of 1,2-DCB in fat. (2) Hepatotoxicity was related to depletion of glutathione (GSH) in the liver. In the model, the consumption of hepatic GSH by metabolism (based on in vivo and in vitro data) and normal turnover was described. In vivo validation was conducted by comparing the predictions of the model with the results of a GSH depletion study performed at two dose levels (50 and 250 mg/kg bw). Subsequently, the GSH consumption by 1,2-DCB metabolites was estimated for man using human in vitro metabolic data. GSH turnover in human liver was assumed to be the same as that in rat. It appeared that at a dose level of 250 mg/kg, hepatic GSH was completely depleted after 10 hr for man, whereas for the rat a maximum depletion of 75% was predicted, after 15 hr. The presented model provides a quantitative tool for evaluating human risk for two different toxicity scenarios, namely covalent binding of reactive metabolites and depletion of GSH. (C) 1997 Academic Press.